During both acute and chronic inflammatory processes, epithelial cells coordinate mucosal responses to infection. For this reason, much recent attention has been paid to understanding innate, anti-inflammatory pathways utilized by mucosal epithelial cells. Of particular interest are small molecules that exhibit anti-inflammatory activity.
The initial encounter of microbes with human tissues and cells occurs at the level of mucosal tissues. Epithelial cells line all mucosal organs, and thus, the epithelium is the key interface for microbial interactions. Importantly, microorganisms which interact with mucosal surfaces may be beneficial (e.g. normal flora) or pathogenic (e.g. infectious agents), and as a result, epithelial cells have adapted mechanisms to selectively kill or inactivate invading microorganisms. As part of this arsenal, epithelial cells express antimicrobial peptides whose primary function includes killing of invading microorganisms. This family of unrelated peptides includes peroxidase, lactoferrin, lysozyme, phospholipase A2, secretory leukoprotease inhibitor (SLPI), and defensins (1). Among the innate anti-inflammatory and/or anti-infective defense molecules of humans is the bactericidal/permeability-increasing protein (BPI), a 55-60 kDa protein found in neutrophil azurophilic granules, on the neutrophil cell surface, and to a lesser extent, in specific granules of eosinophils (2-4). BPI selectively exerts multiple anti-infective actions against gram-negative bacteria, including cytotoxicity through damage to bacterial inner/outer membranes, neutralization of bacterial lipopolysaccharide (endotoxin), as well as serving as an opsonin for phagocytosis of gram-negative bacteria by neutrophils (3, 5). Structural characterization of BPI reveals a symmetrical bipartite molecule containing a cationic N-terminal region for antibacterial and endotoxin neutralization and a C-terminal motif necessary for bacterial opsonization (6).
Therefore, a need exists for the stimulation, production, and/or release of BPI from body tissues to help combat, for example, bacterial invasion and/or infection.